Another way to decrease FC levels within the hepatocyte is to block cholesterol absorption from the gut. 1) Plant stanols (like Benecol – described above) do it by diminishing the FC content in the spherical micelles. 2) CAI (ezetimibe – Zetia) does it by blocking the uptake of FC from the micelles in the first part of the small intestine (duodenum/jejunum). 3) BAS (Questran/Welchol) do it by blocking the absorption of bile acids (made from CE) in the last part of the small intestine (ileum).

The most common of the intestinal-acting agents currently used by physicians is Zetia. Intra-hepatic FC levels are dependent both on the production of cholesterol within hepatocytes as well as the absorption of cholesterol from the gut. Some people are natural "hyper-absorbers" while others are "hyper-producers.’" Most people are probably a degree of both. Zetia has very few side effects and seems quite safe although pregnant/nursing or otherwise potentially child-bearing women and people with ongoing liver problems should probably not take it.

There is some evidence demonstrating that patients taking Statins eventually hyper-absorb cholesterol from their gut as an attempt by the body to return to balance. In this situation, other noncholesterol sterols that are probably even more harmful than cholesterol (sitosterol, campesterol, stigmasterol) may: 1) have their absorption from the gut enhanced by up-regulation of NPC1L1 (see below); and/or 2) have their re-secretion back into the gut and/or bile duct diminished by down-regulation of ABCG5/ABCG8. Noncholesterols sterols seem more atherogenic than cholesterol because there are no human enzymes capable of esterifying them. Any unesterified sterol is quite vulnerable to reactive oxygen species. Esterified cholesterol (CE) is nontoxic and the inactive storage form of cholesterol. Any unesterified noncholesterol sterol (hydrophilic) is trafficked within lipoprotein particle surface coats along with FC (also hydrophilic and usually 20% of total β-lipoprotein cholesterol content). Increased β-lipoprotein FC and/or noncholesterol sterol levels makes the particle more susceptible to oxidation and incorporation into vascular wall macrophages. Patients with CHD tend to have LDL-C levels > 100 mg/dL.  Patients with noncholesterol sterol-induced premature CHD have LDL-sitosterol levels > 30 mg/dL. Thus it appears noncholesterol sterols are at least three times more atherogenic than cholesterol.

Niacin (vitamin B3) works by multiple mechanisms. First and foremost, Niacin decreases the synthesis of large (primarily) VLDL particles and thus leads to reduction of small LDL particle bloodstream levels. 1) Niacin inhibits the enzyme diacylglycerol acyltransferase (DGAT)-2, by which the liver converts free fatty acids (FFA) into TG. 2) Niacin thus decreases resultant intra-hepatic TG levels. 3) Diminished synthesis of TG-rich VLDL particles results. 4) Decreased secretion of large, TG-rich VLDL particles into the circulation occurs. 5) As Niacin is a potent inhibitor of HL, bloodstream levels of small, CE-poor LDL particles are likewise diminished. Niacin should not be taken by individuals with ongoing liver problems or signs of active arterial bleeding. Higher doses of certain forms of dietary supplement Niacin have been shown to cause significant liver inflammation in some individuals.

Niacin also has effects upon HDL particle dynamics. 1) Large HDL particles can bind via surface ApoAI to ApoAI, "holoparticle," catabolic receptors present on hepatocytes (small HDL particles are not well recognized). When large HDL particles bind to these receptors, the entire complex is taken into the hepatocyte and catabolized. 2) Niacin blocks these receptors, thus preventing large HDL particle catabolism (a form of direct RCT). 3) Large, CE-rich HDL particles can exchange CE for TG with TG-rich β-lipoproteins via CETP. 4) CE can thus be returned to the liver by ApoB/E receptors (indirect RCT). 5) Niacin also blocks HL and the resultant large TG-enriched HDL particles remain in circulation. Although no longer capable of conversion to small HDL particles, indirect RCT or SR-B1-related direct RCT, these large TG-rich HDL particles can be removed from circulation by ApoB/E receptors (small particles are not well recognized) if they contain translocated ApoE.

          Niacin was the first agent ever used for lipoprotein disorders as well as the first lipid drug ever studied in terms of CV risk reduction, showing up to 25-30% prevention of otherwise preventable future CV events in a study of hundreds of patients. The only form of Niacin that can be recommended for use is prescription Niaspan (also found in combination with Lovastatin in Advicor). All other forms of Niacin found on the market are dietary supplements without any FDA oversight whatsoever regarding safety, efficacy, quality, content or lot variability. Over-the-counter (OTC) Niacin products (where the FDA would be involved with oversight) DO NOT EXIST in the North American marketplace. Multiple medical authorities have warned against the use of dietary supplement Niacin, basically calling it weak, unsafe junk that "must not be used." The forms of dietary supplement Niacin include: 1) nicotinamide (completely ineffective); 2) immediate-release (poor quality); and 3) sustained release (poor quality, less effective and associated with liver inflammation). For your information, prescription Niaspan is classified as an "extended release" form of Niacin and is safe, effective and of top quality.

     Fibrates are another drug class commonly prescribed for lipoprotein disorders. They have prevented 20-30% of otherwise preventable CV events in clinical outcome studies involving thousands of patients. The safest and most effective Fibrate is probably Tricor. Like Statins and Niacin, Fibrates have multiple mechanisms of action. First and foremost, Fibrates decrease the production and enhance the clearance of VLDL particles. 1) Fibrates decrease intra-hepatic FFA levels available for TG synthesis by promoting their β-oxidation within mitochondia. 2) Fibrates block DGAT2 to decrease the production of TG. 3) Fibrates thus lead to a decrease in intra-hepatic TG levels. 4) Reduction in the production of TG-rick VLDL particles results. 5) Decreased secretion of large, TG-rich VLDL particles into the circulation occurs. 6) As Fibrates decrease ApoCIII and increase both ApoAV and LPL, VLDL particle clearance is enhanced and bloodstream levels of small, CE-poor LDL particles are diminished. Fibrates should not be taken by individuals with liver problems and should be used with caution by individuals with kidney problems.

Fibrates potently decrease VLDL particle production and enhance VLDL particle clearance. 1) Fibrates stimulate various nuclear receptors such as PPARα within many cells, including hepatocytes. 2) This leads to a decrease in the expression of ApoCIII which would otherwise block ApoE recognition by hepatic ApoB/E receptors. 3) The production of ApoAV is also increased which assists in "docking" VLDL particles to hepatic ApoB/E receptors. In this manner, Fibrates directly enhance VLDL particle removal from the bloodstream. Fibrates may also decrease the breakdown of ApoB/E receptors by inhibiting an enzyme known as proprotein convertase subtilisin kexin type 9 (PCSK9). 4) PPARα stimulation promotes the genetic expression of LPL which can thereby remove TG from VLDL particles (in the absence of ApoCIII which would otherwise block ApoCII interaction with LPL). 5) TG is removed from VLDL particles and converted into FFA. 6) The FFA is taken up by muscle cells and metabolized to generate cellular energy. 7) The FFA is also taken up by adipocytes and converted into TG for storage. 8) The FFA also enters hepatocytes. 9) There FFA is metabolized in such a manner as to decrease TG synthesis. 10) Decreased TG levels in the hepatocyte lead to reduced VLDL particle production and secretion.

Fibrates also have potent effects upon HDL particle dynamics. Fibrates directly stimulate PPARα within the nucleus of the hepatocyte. 1) This induces the expression of the ApoAI gene (1) as well as the ApoAII gene (2). Both ApoAI (3) and ApoAII (4) are thus manufactured. 5) Nascent HDL particles containing ApoAI are secreted into the bloodstream. 6) ApoAII assists in the maturation/lipidation of HDL particles after being transferred onto them by various β-lipoproteins. 7) Circulating HDL particles tend to be small on Fibrate therapy since, as soon as they become large and CE-enriched, they are recognized by hepatic SR-B1 receptors (also up-regulated by Fibrate therapy) and rapidly de-lipidated.

Fibrates enhance HDL particle function. 1) Fibrates increase nascent HDL particle release from hepatocytes. 2) These particles penetrate into atherosclerotic plaques where ATP Binding Cassette A1 (ABCA1 – also enhanced with Fibrate therapy) transfers FC from activated macrophages into them in the cardioprotective process of macrophage RCT. LCAT (lecithin cholesterol acyltransferase) converts the FC into CE (with the help of ApoAII – also increased with Fibrate therapy) and the nascent HDL particles become mature. 3) Fibrates up-regulate SR-B1 receptors which recognize and de-lipidate mature large HDL particles in the process of direct RCT. 4) Mature small HDL particles accumulate in the circulation as they are not well recognized by SR-B1 but may re-enter plaque to participate in further macrophage RCT. Note that Niacin can also induce the production and function of ABCA1 within activated macrophages in atherosclerotic plaques (via prostaglandin D-mediated PPARγ activation).

Glitazones (Actos, Avandia) function similar to Fibrates in terms of PPARα stimulation (although they are probably at least four times less potent). Actos is probably the preferable Glitazone since it is equally effective in terms of blood sugar control but seems quite superior in terms of lipoprotein effects. Note that availabe data indicates Actos further lowers total LDL-P while Avandia actually increases it. This may explain some of the recent negative Avandia clinical outcome data.

Omega-3 fish oils function by inhibiting TG synthesis (1) as well as blocking the formation (2) and secretion (3) of large VLDL particles. Prescription Omacor should now be the form used rather than any dietary supplement having no FDA oversight whatsoever regarding safety, efficacy, quality (in terms of whether oxidation of DHA/EPA has occurred – which is what causes fish to smell "fishy"), content (in terms of possible mercury contamination – highest concentrations in king mackerel, shark and swordfish, intermediate in tuna, lower in salmon and lowest in krill) or lot variability.